Gastrectomy Increases the Expression of Hepatic Cytochrome P450 3A by Increasing Lithocholic Acid-Producing Enteric Bacteria in Mice

Abstract

We had previously revealed that drug metabolism, as well as the expression level of hepatic CYP3A, a drug-metabolizing enzyme, increase 12 weeks after gastrectomy in mice. In this study, we elucidated the mechanism of the increased CYP3A expression. The levels of lithocholic acid (LCA)-producing bacteria (Bacteroides fragilis) and LCA in the colon did not show a significant increase up to 4 weeks after gastrectomy compared to the sham operation group. In contrast, at 12 and 24 weeks post-gastrectomy, the levels of Bacteroides fragilis and LCA were significantly higher in the gastrectomy group than in the sham operation group. At 12 and 24 weeks after gastrectomy, the hepatic nuclear translocation of pregnane X receptor (PXR) had also increased. The hepatic CYP3A11 mRNA expression and nuclear translocation of PXR after intraperitoneal administration of LCA to normal mice was significantly higher than those of the control group. The intraperitoneal administration of taurolithocholic acid (TLCA), a taurine conjugate of LCA, caused no change in the expression level of CYP3A11. We suggest that the increase in the expression level of CYP3A after gastrectomy is caused by an increase in the nuclear translocation of PXR, which is triggered by an increase in LCA-producing bacteria.

Intestine farnesoid X receptor agonist and the gut microbiota activate G‐protein bile acid receptor‐1 signaling to improve metabolism

“…3C). Bacteroides are the predominant bacteria in the gut capable of converting TCDCA to TLCA by 7α-dehydroxylase activity, and UDCA to LCA by 7β-dehydroxylase activity (28, 29) . BSH activity in Clostridium de-conjugates TCDCA to CDCA, which is converted to LCA by bacteria 7α-dehydroxylase.…”

“…Acetatifactor grows under strictly anoxic conditions and produces acetate and butyrate. Clostridium and Bacteroides are Gram-positive anaerobic bacteria in the gut with high BSH activity for de-conjugation of TCDCA and TUDCA to CDCA and UDCA, which are converted to LCA by 7α-dehydroxylase and 7β-dehydroxylase, respectively (28, 29, 33) .…”

Normal variation of the gut microbiota affects hepatic cytochrome P450 activity in mice

“…Regarding the influence of “variation” of the gut microbiota on hepatic Cyp, previous research concluded that gastrectomy in mice increased the hepatic expression of Cyp3a and the other major isoform Cyp2b by increasing pH in the gastrointestinal tract and modifying the gut microbiota 12 . Other studies demonstrated that antibiotic‐treated mice, which exhibited disruption of the gut microbiota, displayed lower hepatic Cyp3a and Cyp2b expression 6,7 .…”

Role of pregnane X-receptor in regulating bacterial translocation in chronic liver diseases

“…Lithocholic acid (LCA) is a secondary bile acid, which is considered to be toxic at higher concentrations than the basal levels and is a byproduct of gut bacterial biotransformation process[ 128 ]. Makoto Ishit et al[ 129 ] have shown that upregulation of PXR and its dependent genes happens as an adaptive response to an increase in LCA, in patients who underwent gastrectomy. They reported that gastrectomy shifted the intestinal PH towards alkaline state due to reduced gastric acid, which led to the increased thriving of LCA-producing bacteria and thus leading to increased accumulation of LCA.…”

“…They reported that gastrectomy shifted the intestinal PH towards alkaline state due to reduced gastric acid, which led to the increased thriving of LCA-producing bacteria and thus leading to increased accumulation of LCA. This study highlights that PXR is the foremost physiologic and adaptive sensor of LCA especially considering that FXR another important bile acid sensor is unresponsive to LCA[ 129 ]. More importantly, this study using the example of gastrectomy sets the precedence that other pathologic events, such as dysbiosis may also shift the balance of gut microbiome composition and ultimately influence the bile acid metabolism and the genes they control.…”